Next-generation sequencing study reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes.
Ewelina Elert-DobkowskaIwona StepniakWioletta KrysaKarolina Ziora-JakutowiczMaria RakowiczAnna SobanskaJacek PilchDorota Antczak-MarachJacek ZarembaAnna SułekPublished in: Neurogenetics (2019)
Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Numerous genes linked to HSPs, overlapping phenotypes between HSP subtypes and other neurodegenerative disorders and the HSPs' dual mode of inheritance (both dominant and recessive) make the genetic diagnosis of HSPs complex and difficult. Out of the original HSP cohort comprising 306 index cases (familial and isolated) who had been tested according to "traditional workflow/guidelines" by Multiplex Ligation-dependent Probe Amplification (MLPA) and Sanger sequencing, 30 unrelated patients (all familial cases) with unsolved genetic diagnoses were tested using next-generation sequencing (NGS). One hundred thirty-two genes associated with spastic paraplegias, hereditary ataxias and related movement disorders were analysed using the Illumina TruSight™ One Sequencing Panel. The targeted NGS data showed pathogenic variants, likely pathogenic variants and those of uncertain significance (VUS) in the following genes: SPAST (spastin, SPG4), ATL1 (atlastin 1, SPG3), WASHC5 (SPG8), KIF5A (SPG10), KIF1A (SPG30), SPG11 (spatacsin), CYP27A1, SETX and ITPR1. Out of the nine genes mentioned above, three have not been directly associated with the HSP phenotype to date. Considering the phenotypic overlap and joint cellular pathways of the HSP, spinocerebellar ataxia (SCA) and amyotrophic lateral sclerosis (ALS) genes, our findings provide further evidence that common genetic testing may improve the diagnostics of movement disorders with a spectrum of ataxia-spasticity signs.
Keyphrases
- heat shock
- genome wide
- copy number
- heat shock protein
- amyotrophic lateral sclerosis
- heat stress
- mitochondrial dna
- cerebral palsy
- botulinum toxin
- early onset
- bioinformatics analysis
- genome wide identification
- dna methylation
- end stage renal disease
- upper limb
- electronic health record
- single cell
- newly diagnosed
- oxidative stress
- chronic kidney disease
- genome wide analysis
- spinal cord injury
- machine learning
- gene expression
- cancer therapy
- prognostic factors
- autism spectrum disorder
- big data
- intellectual disability
- real time pcr
- drug induced
- muscular dystrophy